Polynuclear cyclic oxyketones and derivatives thereof and process of making same



Patented Jan. 19, 1943 POLYNUCLEAR CYCLIC OXYKETONES AND DERIVATIVES THEMAKING SAME REOF AND PROCESS OF Leopold Ruzicka, Zurich, and AlbertWettstein, Basel, Switzerland, assignors, by mesne assignments, to CibaPharmaceutical Products, Incorporated, Summit, N, 3., a corporation ofNew Jersey No Drawing. Application June 15, 1936, Serial In SwitzerlandJune 13; 1935 32 Claims. (63. Eta-397.4)

isomeric oxyketones of the saturated or unsaturated andrcstane-series,whose hydroxyl and keto-groups in comparison with the compounds of theandrosterone series are interchanged, are not yet known.

This invention is based on the observation that such new oxyketones andtheir esters are obtainable by partially saponifying a di-ester of adiol of the type of the saturated or unsaturatedandrostane-diols-(3:l7), oxidizing the free carbinol-group (in3-pos1tion) thus produced (it necessary with temporary protection of theden bie bonds present) to a keto-group and, if desired, purifying andsaponifying the keto-ester thus obtained.

A particularly advantageous procedure consists in starting from a mixeddi-ester of a diol of the type of the saturated or unsaturatedandrostane-diols, particularly those esters in which the hydroxyl groupin 3-position is esterifled with an acid radical which is comparativelyeasily saponifiable, whilst that in ll-position is esterified by an acidradical which is saponifiable with comparative difficulty. One can alsostart from a free diol, partially esterify this and oxidise theresulting diol, mono-esterified in 17 position, in the manner describedabove, advantageously after purification.

The same oxyketones can be produced by subjecting the free diol, ifdesired with temporary protection of double bonds present, directly to apartial oxidation and separatingfrom the reaction product the compoundwhich has undergone oxidation at the 3-position.

Finally, it is also possible to obtain these new oxyketones bysubjecting to a partial reduction at diketone of the type of theandrostane-dione- (3:17) and separating from the reduction product the3-keto-17-oxy-compound.

The carbinol-group in 3-position can also be oxidized to a keto-group bythe action of a dehydrogenating agent.

The various methods may be illustrated by the following formulae, inwhich A01 and A02 mean the same or different acyl radicals and Rrepresents hydrogen or a monovalent hydrocarbon radical:

CH3 CH3 CH: CH;

R R I -Ac: OH i H AIM-0 V H0 V w I l l! partial saponlfication partialesterillcation i. CH3 CHa CH3 CH2: P I 0-Acz 3 0Acr oxidation or k I d hl e y o- HO genation 0 V III IV esteriflcati% seponiflcation CH; OH: R

i on

VII

partial oxidation or dehydrogenatio/ partial reduction CH3 CH8 R CHa CHI0H /\U-o H \J V VI vthe oxidation of an unsaturated diol or its ester toan oxyketone or its ester the carbon double linkage is advantageouslyprotected from the action of the oxidizing agent, for example by theattachment of halogen or hydrogen halide; after oxidation the halogen isthen again removed, for example by treatment with zinc in glacial aceticacid or benzene, with catalytically activated hydrogen or with an alkaliiodide, or the hydrogen halide is again removed by treatment with analkaline agent such as a tertiary base. The conversion of the free diolsinto 3-keto-1'l-oxy-compounds by oxidation of the 3-carbonol-groupproceeds in a particularly advantageous manner in cases in which thenuclear carbon atom in 17- position is linked to a hydrocarbon radical.

When a mixed di-ester is to be subjected to partial saponiiicatlon thereare advantageously used those which contain in 3-position the radical ofa lower fatty acid such as acetic acid or formic acid, and inl'l-position the radical of a higher fatty acid such as a valeric acid,or a carbamic acid, benzoic acid, a tolulc acid, hexahydrobenzoic acidor a hydrohalogen acid.

The aforesaid mixed di-esters are obtained by causing to act on a3-mono-ester of a dial of the type of the saturated or unsaturatedandrostane diols an acylating agent containing an acid radical differentfrom that already present in the molecule of the mono-ester.

The partial saponiilcation may be conducted, for example, in methylalcohol, ethyl alcohol, in a higher alcohol, in dioxane, acetone or thelike. If an alcohol is used re-esterification generally occurs inaddition to the actual saponification, so that the quantity of alkalisolution consumed is frequently considerably less than the calculatedquantity. One is therefore not restricted to the use of the calculatedquantity of alkali, but may use a larger or a smaller quantity. By' thismeans, as well as by the concentration of the alkali solution and thetemperature, the duration of the reaction may be favorably influenced.

Suitable acylating agents for converting II into III and for convertingVII into IV are, for instance, acids, acid halides and acid anhydrides,for example benzoic acid, acetic acid, formic acid, benzoyl chloride,acetyl chloride, acetic anhydride and the like, if required in thepresence of an acid binding agent such 'as a tertiary base or an alkali.Particularly when an' acid halide or an acid anhydride is used there isadvantageously taken for the partial esterification of II only aquantity of acylating agent suflicient for esterifying onehydroxyl-group.

In the partial reduction of VI the hydrogenation is interrupted whenthere has been absorbed a quantity of hydrogen suiiicing for thereduction of one carbonyl-group.

For the dehydrogenation of the carbinol-group to the keto-group theremay be used with advantage any of the usual dehydrogenating agents, forinstance selenium, sulfur, or a metallic catalyst belonging to the groupof hydrogenating or dehydrogenating catalysts such as copper, platinum,palladium, gold, nickel and the like, if desired in the presence of ahydrogen acceptor such as naphthalene, phenol, cinnamic acid, fumaricacid or the like.

It is easily possible to isolate in a pure form the oxyketone producedeither by direct crystallizae tion or by preparing a suitablederivative. Such,

derivatives are obtained, for example, by reaction with the usual ketonereagents such as semi-carbazide, thiosemicarbazide, hydroxylamine,aminoguanidine, phenylhydrazine and its substitution products, neutralvor basic acylhydrazldes. For purification and separation acylation isoften useful, for example by means of acetic anhydride, benzoylchloride, dinitro-benzoyl chloride or the like. By the action ofhydrolytically acting agents the above compounds can be split into theircomponents. For separating the 3-keto-compound from any 3-oxy-compoundwhich may have been formed .as a by-product there have been provedadvantageous also the saponines such as digitonin, especially when thesteric arrangement of the hydroxyl-group in 3- position corresponds withthat of cholesterol.

Among the diols of the type of the saturated or unsaturatedandrostane-diols-(3:l7) there are to be understood not only thestereo-isomeric androstane-diols in question themselves, but also theirnuclear substitution products, for example the compounds substituted in17-position by a hydrocarbon radical such as an alkyl-,aralkyloraryl-group; so also the scope of the 3:17-

androstane-diones extends also to the isomeric 3:17-aetiocholanediones.The following diols, for example, are suitable parent materials for theinvention: the androstane-diols-(31l7), the A or A-androstene-diols-(3:17), the 1'!- methylorl'I-ethyl-androstane-diols-(3:l7) the 3.76 grams ofandrostane-diol-(3J7) -diacetate of the formula CH: CH

of melting point 127-128 C. are allowed to stand for 48 hours at roomtemperature in 1000 cc. of n/lOO-methyl-alcoholic potash solution. Afterconcentrating the solution, the l'I-acetoxy-androstane-ol-(B), producedby the partial saponification, is precipitated by addition of water,filtered, washed with water and dried in a vacuum over phosphoruspentoxide. It may be used without further purification for makingandrostane-ol-(17)-one-(3). For this purpose the product is dissolved in50 cc. of glacial acetic acid and there is added, while cooling, asolution of 0.8 gram of chromium trioxide in 25 cc. of acetic acid ofper cent. strength. After standing for 14 hours at room temperature somediluted with water and the precipitate formed dissolved in ether. Theethereal solution is washed with dilute sodium carbonate solution andwater and evaporated. From the residue the acetate 01androstane-ol-(l'l) -one-(3) is isolated, preferably by means of thesparingly sol- CHa OH:

By recrystallization from hexane or dilute alcohol the latter may bepurified. It forms colorless crystals of melting point 182 C.

Instead of the acetate there may also be used the propionate or thebutyrate.

Example 2 3,74 grams of A =-androstene-diol-(3:17)- diacetate of theformula of melting point 165-166 C., in which the two hydroxyl groupsare probably in trans-configuration, are allowed to stand at roomtemperature for 40 hours in 1000 cc. of methyl alcohol to which havebeen added previously 0.45 gram of potassium hydroxide. Afterneutralizing, the solution is strongly concentrated in a vacuum and thenthe crude A -17-acetoxy-anclrostene ol-(3), which has been produced bypartial saponification, is precipitated by addition of water, extractedwith ether and obtained by evaporation of the ether. The crudemono-ester thus obtained is purified by recrystallization from hexane,with removal of sparingly soluble constituents and the purified ester ofmelting point 146-148" C. is taken up in 50 cc. of glacial acetic acidand, while cooling, there is added, drop by drop, a solution of brominein glacial acetic acid as long as there is immediate decolorization.Finally, also in the cold, there is added 1 gram of chromium trioxidedissolved in 30 cc. of acetic acid of 90 per cent. strength and thewhole is allowed to stand over-night at room temperature. The whole isthen poured into 1 liter of water, the precipitated product is filteredand washed with much water. The brominated ketone thus obtained isdissolved for the purpose of debrominating it in 50 cc. of glacialacetic acid, and after addition of 20 grams of zinc dust the whole isheated while vigorously shaking for 12 minutes on the boilingwater-bath. There follow filtration through a glass filter, washing witha little hot glacial acetic acid, precipitating the solution with waterand extraction with ether. The ethereal solution is washed with dilutesodium carbonate solution and water and then evaporated to yield aresidue, from which A androstene-ol-(17) -one-(3)-acetate may beisolated by means of its semicarbazone, and after recrystallization fromhexane melts at 141 C. By saponiflcation it may be converted into thefree oxyketone, namely A androstene-ol-(1'7) one- (3) oi! the formulaCH: CH:

which melts at 155 C. When using other esters, there are obtained thecorresponding keto-esters in an analogous manner, for instance A-androstene-ol-(1'7 -one-(3) -benzoate of melting point 194-195 (3.:

. Degrees C. The propionate of melting point 121-123 The n-butyrate ofmelting point 111-113 The iso-butyrate of melting point 131-133 Then-valerianate of melting point 109-111 The n-caprinate of melting point57 The palmitate of melting point 72- 74 The stearate of melting point79- 80 which esters may be saponified, if desired.

The double linkage may be protected by chlorine, for example, instead ofby bromine.

Example 3 1.87 grams of A -3-trans-17-cis-androstenediol-diacetate ofthe formula CHz CH:

C....CO.O

of melting point 168 C. are dissolved in 370 cc.-

' orated. By fractionally crystallizing the residue from hexane, thel'l-mono-acetate of A -3- trans-17-cis-androstene-diol is obtained. Thisis dissolved in 30 cc. of glacial acetic acid and treated with thecalculated quantity (1 mol) of bromine in glacial acetic acid. Thebromine is immediately decolorized. There is then added a solution of 1mol of chromic acid in acetic acid of per cent. strength and the wholeis allowed to stand over-night at room temperature. The reaction productis then precipitated by addition of water, filtered, debrominated byshaking in an alcoholic solution for 48 hours with zinc dust and finallypurified by recrystallization from hexane. From the acetate of A-androstenecis-ol-(17)-one-(3) of melting point C. there is obtained bysaponification with methyl alcoholic potash of 2v per cent. strength theA -androstene-Cis-ol-(l'l)-one-(3) of the formula Example 4 2.31 gramsof A -3-trans-l'l-trans-androstene-diol-B-acetate-l'l-benzoate of theformula CH3 CH3 of melting point Fla-180 C. are mixed with 500 cc. ofmethyl alcohol. The mixture is stirred for a long time (about 50 hours)at room temperature and there is added, gradually by drops, a methylalcoholic solution of 0.3 gram of potassium hydroxide. Afterneutralization the whole is highly concentrated in a vacuum; the crudeproduct is precipitated by the addition of water, extracted by means ofether and the ethereal solution is evaporated. The residue iscrystallized from hexane, yielding brilliant needles By saponiilcationwith alcoholic potash this benzoate may be converted into the freeoxyketone, namely 1 A" -androstene-trans-ol-(i'l)- one-(3) of theformula CH: CH

of melting point 155 C.

In a similar manner by partial saponification of A -3-trans-17-cisandrostene diol-3-acetate-1'7-benzoate of melting point 133434 0.,oxidation of the A -3-trans-l'l-cis androstenediol-l'I-benzoate ofmelting point 150-151" C.

of melting point 222-223 C. of the A-3-transl7-trans-androstene-dio1-17-benzoate.

This mono-ester is dissolved in 50 cc. of glacial acetic acid and thereis added, while cooling and in drops, the calculated proportion of asolution of bromine in glacial acetic acid. Finally, 0.5 gram ofchromium trioxide dissolved in 15 cc. of acetic acid of 90 per cent.strength is added in the cold and the whole is allowed to standover-night at room temperature, during which time the oxidation productin part crystallizes. The mass is ,then poured into water, theprecipitated matter filtered and washed with much water. The brominatedketone thus obtained is debrominated by violent agitation with zinc dustin glacial acetic acid on the boiling water-bath. The mass is thenfiltered, washed and the solution precipitated by means of water. Theprecipitate is extracted with ether, the ethereal solution shaken withdilute sodium carbonate solution and water and evaporated. It is alsopossible to debrominate the brominated ketone by heating a dry solutionof it in benzene with an alcoholic solution of sodium iodide. In thiscase the solution is subsequently washed with aqueous sodium sulfitesolution and water and evaporated.

From the crude product made by one or the other of these methods may beobtained, for instance by recrystallizing it from hexane or bysublimation in a high vacuum or by both methads, or by mean of thesparingly soluble semicarbazone, the A -androstene-trans-ol-(1'7)one-(3) -benzoate of melting point 193-194 C.

and subsequent saponification of the A -androstene-cis-ol- 17) -one- (3)-benzoate of melting point -136 C. there is obtained the A -and--rostene-cis-ol-(1'7)-one-(3) described in Example 3.

Instead of chromic acid, copper oxide for example ,can be used foroxidizing the androstenediol-l'I-benzoate.

Example 5 Into 1 liter of ethyl alcohol which has been preheated to 30C. there are introduced first 5 grams of A-androstene-3:1'7-diol-3-acetate- 17-benzoate of the formula CH: CH:

of melting point 17 8-180 C. and then one molecular proportion of anethyl alcoholic potash solution (containing 0.64 gram of potassiumhydroxide) and the whole is thoroughly stirred for 4 hours at theaforesaid temperature. The solution is neutralized (the quantity ofalkali consumed amounting to about 10 per cent.) and then highlyconcentrated in a vacuum and the crude product is shaken with water andether, the ethereal solution is separated and evaporated. Bycrystallizing the residue from isopropyl ether A-androstene-3;1'7-cliol-1'7-benzoate is obtained in the form ofbrilliant needles of melting point 222-223" C.

This mono-ester is oxidized with chromic acid,

after bromination in glacial acetic acid, in a manner analogous to thatdescribed in Example 1. For debrominating the brominated ketone thusobtained the ketone is dissolved in benzene, the solution is carefullydried and then boiled for 3 hours in a reflux apparatus together with asolution of sodium iodide in absolute alcohol. The reaction mixture ispoured into a sodium sulfite solution of 2 per cent. strength,-thebenzene layer which separates is removed, shaken I further with a sodiumsulfite solution and with a bicarbonate solution and then evaporated. Itis also possible to debrominate the brominated ketone, for example, bythe action of zinc in glacial acetic acid or in a mixture of benzenesolution and with water and then evaporated. The crude A-androstene-3-one-17-ol-benzoate oi the formula 2.1 grams ofandrostane-diol-(3:17) of the rormula CH3 CH3 of melting point 223 C.are heated in 100 cc. of acetic acid of 90 per cent. strength for 8hours on the water-bath, and then allowed to stand overnight at roomtemperature. The reaction product is precipitated with water, pressedand dried in a vacuum over phosphoruspentoxide. By systematicallytreating it with benzine (boiling range YO-80 C.) it is separated intosparingly soluble and more easily soluble fractions. The sparinglysoluble fraction is unchanged diol. By recrystallization of the moreeasily soluble fraction from dilute alcohol there is obtained thel'I-mono-acetate of androstane-diol-(3z17) which melts at 192 C. Thisester is oxidized in the manner described in Example 1, and if requiredthe oxidation product is saponified to yield androstane-ol-(l'l)-one-(3)of the formula CHa CH:

0 of melting point 182 C.

Example 7 2.9 grams of A -androstene-diol-(3zl7) of the formula CH3 CH3dine. The reaction mixture is poured into water, the pyridine isneutralized by addition of an acid, the precipitated crude product isextracted with ether and the etheral solution is washed and evaporated.Fractional crystallization of the residue from hexane yields pure A-17-acetoxyandrostene-ol-(3) of melting point 146-148 C. The mono-esterso obtained is brominated, oxidized with chromic acid in glacial aceticacid and debrominated with zinc duct and acetic acid in the mannerdescribed in Example 2, whereby there is obtained the keto-ester, namelyA -androstene-ol(17) -one-(3) -acetate of melting point 141 0., which ifrequired can be converted by saponification into the A-androstene-ol-(17) -one-(3) of the formula (F of of melting point C.

In an analogous manner by partial benzoylation instead of acetylationA=-androstenedid-(3:17) can be converted by way of its 17- mono-benzoateof melting point 222-223 G. into the A -androstene-ol-(17) -one-(3)-benzoate of melting point l94-195 0.; if required the latter can beconverted by saponiflcation into the above described A-androstene-ol-(17)- one-(3) of melting point 155 C.

Example 8 2 grams of A -androstene-Ii:17-diol-17-benzoate of the formulaof melting point 222-223 0., obtainable as an intermediate product inthe process of Examples 4, 5, and '7, and 2 grams of copper powder areheated at 225 C. in a vacuum until evolution of gas has ceased. The massis then treated with 20 cc. of alcohol, the solution filtered, the solidmatter washed and the filtrate is poured into 200 cc. of water andextracted with ether. The ethereal solution is washed with sodiumcarbonate solution and water and evaporated. From the residue the A-androstene-ol-(17)- one-(3) -benzoate of melting point 193494 C. isisolated, for example by re-crystallization from isopropyl ether and/orsublimation in a high vacuum or by conversion into its sparingly solublesemi-carbazone. By saponification with alcoholic alkali solution thebenzoate is converted into the free oxy-ketone, namely A-androstene-ol-(17)-one-(3) of the formula CHa 2 grams ofandrostane-3:l'l-diol-l'l-acetate of the formula CH: CHI H no of meltingpoint 192' C., obtainable as an intermediate product in the process ofExamples 1 and 6, and 2 grams of cinnamic acid are dissolved in 100 cc,of glacial acetic acid and the solution is shaken while warm with apalladium catalyst. When the reaction is atan end the catalyst isfiltered and the filtrate is poured into 800 cc. of water and the liquidis extracted with ether. The ethereal solution is washed with water,dried and evaporated in a vacuum. The residue is saponifled while warmwith alcoholic alkali solution of 2 per cent. strength and thesaponification mixture is poured into water and the whole extracted withether. The ethereal solution is washed repeatedly with sodium carbonatesolution and then with water, whereafter it is evaporated in a vacuum.From the residue androstane-ol-(l'li-one-w) of the formula on; on. E

of melting point 182 C. is obtained, for example by recrystallizationand/or sublimation in a high vacuum, or by conversion into a sparinglysoluble derivative, such as the semicarbazone or dinitrophenylhydrazonederivative.

Instead of a mixture of androstane-diol-l'lacetate and cinnamic acidthere may be used an androstane-Ii:l'l-diol-l'l-cinnamic acid ester, inwhich the hydroxyl group to be dehydrogenated and the hydrogen acceptorare united in the same molecule.

-CO-CH:

Example 3.06 grams of I'T-methyl-androstane-diol- (3:17) of the formulaCH; CH: OH (W H I no of melting point 185 C. are dissolved in 50 cc. ofglacial acetic acid and, at room temperature, there is added in drops asolutioii of 0.8 gram of chromium trioxide in 50 cc. of glacial aceticacid. The chromic acid is somewhat rapidly consumed; the whole isallowed to stand for 3 hours at room temperature, then poured into waterand the product thus precipitated is dissolved in ether. The etherealsolution is washed with dilute caustic soda solution and water and driedover anhydrous sodium sulfate. From the strongly concentrated etherealsolution the l'l-methylandrostane-ol-(l'l)-one-(3) of the formula cm cmcrystallizes. By recrystallization from dilute alcohol it is purifiedand then melts at 192 C. The

semicarbazone obtained in the usual manner with compounds containing inthe ill-position a substituted hydroxyl group, such as an acyloxy or analkoxy-group.

Example 11 3.04 grams of A '-l'l-methyl-androstene-diol- (3:17) of theformula of melting point 202-204 C. are dissolved in 50 cc. of glacialacetic acid and mixed with a solution of 1.6 grams of bromine in 10 cc.of glacial acetic acid. To this solution there is added, by drops, oneof 0.8 gram of chromium trloxide in 50 cc. of glacial acetic acid. Afterseveral hours standing at room temperature the whole is poured intowater, the precipitated dibromide is filtered, washed and treated inglacial acetic acid solution with 3 grams of zinc dust. The filteredsolution is then poured into water and the precipitated A-1'7-methy1-androstene-ol- (17) -one-(3) of the formula H I C I OH: Cm

acylated in 17-position or substituted in another manner.

Example 12 2.88 grams of androstane-dione-(Zizl'?) of the formula C H;CH;

V may be separated from it with the aid of digitonin or by way of thesemicarbazone and recrystallized from hexan or dilute alcohol forpurificatioh.

Example 13 2.86 grams of A -androstene-dione-(3:17) of the formula ofmelting point 173-174" C. are dissolved in alcohol and hydrogenated withthe aid of a nickel catalyst. When the amount of hydrogen calculated forone molecule has been absorbed hydrogenation is interrupted, thecatalyst is filtered from the solution and the latter is poured into 400cc. of water. The mass is extracted with ether and th ethereal solutionis washed with water and evaporated in a vacuum. The residue isesterified by heating for a short time with a few cc. of aceticanhydride; the latter is then evaporated and the residue fractionallycrystallized from dilute acetone. In this manner one obtains the A-androstene-ol-(1'7) -one-(3) -acetate of melting point 141 C. Bysaponification the corresponding free oxy-ketone is produced, namely A-androstene-o1-(17)-one-(3) of the formula on on,

NW of melting point 155 What we claim is:

1. The 3-keto-cyclopentano-;polyhydro-10.13- dimethyl-phenanthrenescontaining a carbon double bond and in the 1'7-position the group 5CH-R, wherein R is a group which is hydrolizable to hydroxyl.

2. The compounds of the formula CH3 OH; H

is A I' wherein R is a group which is hydrolizable to hydroxyl.

3. The compounds of the formula cm on;

wherein Ac stands for an acyl group. The compound of the formula CH OH;H

forming colorless crystals of melting point 194- 195 C.

5. A process for the manufacture of a compound of thecyclopentano-polyhydro-10,13- dimethyl-phenanthrene series, comprisingoxidizing the 3-carbinol group of acyclopentanopolyhydrophenanthrene-Zi,1'7-diol to a keto group afterprotection of the hydroxyl group in the 17-position by a radical whichis unaffected by oxidizing agents but reconvertable into a hydroxylgroup by first substituting both hydroxyl groups of the diol, and thenreconverting the substituted hydroxyl group in the 3-position to a freehydroxyl group.

6. A process for the manufacture of a compound of thecyclopentano-polyhydro-10,-13-

dimethyl-phenanthrene series comprising oxidizing the B-carbinol groupof a cyclopentanopolyhydrophenanthrene-2,17-dio1 to a keto group afteracylation of the hydroxyl group in the 17- position by first acylatingboth hydroxyl groups of the diol, and then hydrolizing the acylatedhydroxyl group in the 3-position only.

7. A process for the manufacture of a compound of thecyclopentano-polyhydro-10,13-dimethyl-phenanthrene series, comprisingoxidizing the B-carbinol group of acyclopentanopolyhydrophenanthrene-B,17-diol to a keto group afterprotection of the hydroxyl group in the 17- position by a radical whichis unaffected by oxidizing agents but reconvertable into a hydroxylgroup by first substituting both hydroxyl groups of the diol withdifferent substituents so that the substituent in the 3-position is moreeasily hydrolizable than the substituent in the 17-position, andafterwards hydrolizing the substituent in the 3-position.

8. A process for the manufacture of a compound of thecyclopentano-polyhydro-10,13-dimethyl-phenanthrene series comprisingoxidizing the 3-carbino1 group of acyclopentanopolyhydrophenanthrene-3,17-dio1 to a keto group afteracylation of the hydroxyl group in the 1'7-position by firstsubstituting both hydroxyl groups of the diol with different acyl groupsso that the acyl group in the 3-position is more easily hydrolizablethan the acyl group in the l7-position, and afterwards hydrolizing theacyl group in the 3-position.

9. A process for the manufacture of a compound of thecyclopentano-polyhydro-10,-13-dimethyl phenanthrene series comprisingoxidizing the 3-carbino1 group of acyclopentanopolyhydrophenanthrene-3,17-diol to a keto group afteracyiation of the hydroxyl group in the l'l-position by acylating with adiificultly hydrolizable acyl group the 17-hydroxyl group of the diol,the hydroxyl group in the 3-position of which is already acyiated by aneasily hydroiizable group, and afterwards hydrolizing the acylatedhydroxyl group in the 3position.

10. A process for the manufacture of a compound of thecyciopentanopolyhydrophenanthrene series, comprising acylating bothhydroxyl groups of a diol of the formula CH; CH, H:

hydrolizing the acylated hydroxyl group in the 3-position only, andoxidizing the S-carbinolgroup to a keto-group.

11. A process for the manufacture of a compound of thecyclopentanopolyhydrophenanthrene series, comprising acylating bothhydroxyl groups of a diol of the formula threne series, comprisingacylating both hydroxylv groups of the compound of the formula CH; OH: H

hydrolizing the acylated hydroxyl group in the 3-position only, andoxidizing the 3-carbinol group to a keto group.

14. A process for the manufacture of a compound of thecyclopentanopolyhydrophenanthrene series, comprising acylating bothhydroxyl groups of the compound of the formula hydrolizing the acylatedhydroxyl group in the 3-position only, and oxidizing the 3-carbinolgroup to a keto group with temporary protection of the carbon doublebond present.

CHIH

15. A process for the manufacture of a compound of thecyclopentanopolyhydrophenanthrene series, which comprises acyiating bothhydroxyl groups of the compound of the formula CHI CIIa

hydrolyzing the acylated hydroxyl group in the 3-position only, addinghalogen to saturate temporarily the double bond, oxidizing the3-carbin01 group to a keto group, and treating the product with'ahalogen eliminating agent to restore the double bond.

16. A process for the manufacture of a'compound of thecyclopentanopolyhydrophenanthrene series, comprising acylating bothhydroxyl groups of the compound of the formula hydrolizing the acylatedhydroxyl group in the group.

18. A process for the manufacture of a compound of thecyclopentanopolyhydrophenanthrene series, comprising benzoylating thel'l-hydroxyl group of the compound of the formula CH; CH;

II OH I CHa.C (LO-V hydrolizing the acetylated hydroxyl group, andoxidizing the 3-carbinol group to a. keto group.

19. A process for the manufacture of a compound. of thecyclopentanopolyhydrophenanthrene series, comprising benzoylating the17-hydroxyl group of the compound of the formula CH3 CH3 n on H lCH:.C0.0

CH: CH;

hydrolizing the acetylated hydroxyl group, and oxidizing the 3-carbinolgroup to a keto group with temporary protection of the carbon doublebond present.

21. A process for the manufacture of a compound of thecyclopentanopolyhydrophenanthrene series, comprising benzoylating the17-hydroxyl group of the compound of the formula DJ omo 0.0

hydrolizing the acetylated hydroxyl group, oxidising the 3-carbino1group to a keto group with temporary protection of the carbon doublebond present, and hydrolizing the benzoylated hydroxyl group with analkaline agent.

22. A process for the manufacture or a com pound of thecyclopentanopolyhydrophenanthrene series, comprising benzoylating thel7-hydroxyl group of the compound of the formula CH: OH: H

hydrolizing the acetylated hydroxyl group, oxidizing the B-carbinolgroup to a keto group with temporary protection of the carbon doublebond present, and hydrolizing the benzoylated hydroxyl group with analkaline agent, in the presence of an aliphatic alcohol.

23. A process as claimed in claim 22, wherein chromic acid is usedas'the oxidizing agent.

24. A process for the manufacture of a compound of thecyclopentanopolyhydrophenanthrene series, comprising acetylating bothhydroXyl groups or the compound of the formula CH: CH:

hydrolizing the acetylated hydroxyl group in the 3-positoin only,oxidizing the 3-carbinol group to a keto group with temporary protectionof the carbon double bond present, and then hydrolizing the acetylatedhydroxyl group in the 17-position.

25. The compound of the formula CH: CH: H

X/IJ (LCO.CH:

forming colorless crystals of melting point 141 C.

26. In the process of preparing male sex hormones, the step of treatingtestosterone having the formula CmHzsOz and the configuration I ti withan acylating agent under conditions producing esterification.

27. Method for the production of 17-hydroxy- 3-keto compounds of thecyclopentano polyhydrophenanthrene series, comprising subjecting acompound 01. the cyclopentano polyhydrophenanthrene series of thegeneral formula ClQHnRlRZX, wherein n stands for an even number from 26to 28, inclusive, and R1 represents a free secondary alcoholic group atthe carbon atom 3, wherein R2 is at the 17-position and stands for amemher of the group consisting of a hydroxyl group and groups that canbe transformed into a secondary alcoholic group with the aid ofhydrolysis, while X is likewise at the 17 position and indicateshydrogen, to the action or an oxidizing agent capable of transforming asecondary alcoholic group into a kei'n group.

28. Method according to claim 2'1, wherein a hexavalent chromiumcompound is used as the agent for the transformation of the secondaryalcoholic group into the hate group.

29. Method according to claim 27, wherein the carbon-to-carbon doublebond of an unsaturated dihydroxy starting compound is protected from theaction or the oxidizing agent by intermediary addition of halogen tosaturate the double bond.

30. llethodaccordingtoclaimz'i, andisolating the hydroxy-keto compoundsthe oxidation mixture by means or keto reagents.

31. Method according to claim 27, and isolating the hydroxy-ketocompounds from the oxidation mixture by means oi! acylating agentscapable of forming diflcultly soluble esters.

32. The I'I-benzoate of testosterone,

. moron) nuzrcxa. amm'r wm'rs'mm.

